Pathology Of The Liver And Gallbladder Flashcards
What is acute liver failure
Acute liver illness associated with encephalopathy and coagulopathy that occurs within 26 week of the initial liver injury in the absence of pre-existing liver disease.
•Most patients progress to coma within a week.
•Its is useful to know the interval between onset of symptoms and liver failure as this can point to the aetiology.
•Very rapid onset (formerly called fulminant hepatitis): due to drugs, toxins causing massive hepatic necrosis. Usually acetaminophen, but also autoimmune hepatitis, Hep A,B and E.
•Injury may be due to direct toxic injury or immune mediated.
•Rare causes include cancers (lymphoma, leukemias), abnormalities of blood flow, metabolic disorders.
What is ascites
Occurs due to cirrhosis in 85% cases.
•Detected clinically at >500ml of fluid
•It is usually a transudate
•Can seep through trans-diaphragmatic lymphatics to cause hydrothorax, particularly on the right
What are portosystemic shunts
eins around and within the rectum (manifest as hemorrhoids)
•Esophagogastric junction (producing varices)- bleeding leads to and death in 50% of cases
•Retroperitoneum and the falciform ligament of the liver (involving periumbilical and abdominal wall collaterals)-Caput medusae
What is splenomegaly
Enlargement up to 1000g
•May induce hypersplemism
•Sequestrates blood elements in expanded red pulps
What is hepatopulmonary syndrome
•Seen in 30% of patients with cirrhosis and portal hypertension
•Caused by the dilatation of intrapulmonary capillary and precapillary vessels
•Causes right to left shunting of blood leading to V/Q mismatch and hypoxemia which worsens in the upright position.
•Thought to be caused by reduced hepatic clearance of endothelin-1 which stimulates NO production.
What is portopulmonary hypertension
Pulmonary arterial hypertension arising in liver disease.
•Concomitant portal hypertension and excessive pulmonary vasoconstriction and vascular remodeling.
•Causes dyspnea on exertion and finger clubbing.
What is acute on chronic liver failure
Rapid hepatic decompensation in a patient with chronic hepatic failure.
•Hep D on chronic Hep B, or mutant Hep B on chronic hep B.
•Rapid weight loss or malnutrition in the patient with nonalcoholic hepatosteatosis
•Other causes are sepsis, acute cardiac failure or malignancy.
What is hepatitis A
Nonenveloped, positive strand RNA picornavirus
•Self limiting without chronicity
•Transmission is feco-oral although sexual transmission is possible
•The receptor for HAV on hepatocytes is HAVcr-1 (also known as TIM-1)
•It has no cytopathic effect
•Injury is caused by cytotoxic T-lymphocytes and NK cells
Incubation period is 2 to 6 weeks
•IgM appears with symptoms IgG appears during recovery conferring lifelog immunity.
•Complications include acute liver failure (0.1-0.3% of cases), cholestsasis, relapse, and immune mediated leukocytoclastic vasculitis, glomerulonephritis and cryoglobulinemia.
What is hepatitis B
Hep B may present as:
•Acute hepatitis followed by recovery and clearance of the virus
•Acute hepatic failure with massive liver necrosis
•Chronic hepatitis with or without progression to cirrhosis
•Asymptomatic, “healthy” carrier state
Prevalent in Africa, Asia and Western Pacific rim
•Has a parenteral mode of transmission as well as horizontal transmission
•Hepadnaviridae
•The virus has the following proteins:
•Hepatitis B surface antigen: envelope glycoproteins
•Hepatitis B core antigen: nucleocapsid protein
•Hepatitis Be Antigen: nuclear polypeptide
•HBV polymerase: DNA pol and reverse transcriptase
•Hepatitis B X protein: transcription transactivator: plays a role in hepatocellular carcinoma
Although cytopathic effect exists, most disease is caused by the host immune response.
•Strong interferon response by CD4+ and CD8+ cells is important for resolution of acute infection
•HBsAg: persists with viremia, present in chronic liver disease
•Anti-HBs: appears on resolution, denotes immunity
•IgM anti-HBc: Acute infection
•HBeAg, HBV DNA, HBV DNA pol: active replication, infectivity and chronicity
•Anti-Hbe: waning acute infection, not formed in chronic infection
Anorexia, fever, jaundice, and upper right quadrant pain
•Glomerulonephritis, polyarteritis nodosa- immune complex mediated
•Rarely acute liver failure occurs
•5-10% become chronic, chronicity and eventually hepatocellular carcinoma is inversely proportional to age of patient
•Vaccination is effective
•Treatment is with interferons and reverse transcriptase inhibitors
What is hepatitis C
It is the most common chronic blood-borne infection
•Flaviviridae family, genus Hepacivirus
•Parenteral and horizontal modes of transmission
•Pathogenesis:
•HCV RNA polymerase has poor fidelity leading to genomic instability & antigenic variability within one individual
•Evasion of IFN-mediated anti-viral response and repeated bouts of hepatic damage
What is hepatitis D
Hepatitis delta virus
•Replication is defective in the virus hence it causes infection only when encapsulated by HBsAg
What is autoimmune hepatitis
Chronic hepatitis of variable severity, histologically indistinguishable from chronic viral hepatitis
•Patients have variety of immunologic abnormalities
•Female predominance (70%)
•No serologic viral markers
•Elevated serum IgG >2.5 gm/dl
•High titers of autoantibodies (80%) including ANA, anti-smooth muscles. Increased frequency of HLA-B8 or HLA-DRw
•Other forms of autoimmune diseases may be present (60%), e.g. RA, Sjogren’s syndrome
•Overall risk for cirrhosis is 5%
•Rx: good response to immunosuppressive therapy
What is alcoholic liver disease
Alcohol is the fifth leading cause of death in the U.S. (many related to automobile accidents)
•3 forms of alcoholic liver disease:
• Hepatic steatosis
• Alcoholic hepatitis
• Alcoholic cirrhosis
What are the three forms of alcoholic liver disease
• Hepatic steatosis
• Alcoholic hepatitis
• Alcoholic cirrhosis
What is the pathogenesis of alcoholic liver
Alcohol-induced hepatocellular steatosis:
•Generation of excess NADH by alcohol dehydrogenase and acetaldehyde dehydrogenase leading to increased lipid biosynthesis
•Impaired assembly & secretion of lipoproteins
•Increased peripheral catabolism of fat
Alcohol-induced hepatocellular damage:
•Induction of cytochrome P-450
•Generation of free radicals
•Direct effect on microtubular and mitochondrial function and membrane fluidity
•Acetaldehyde induces lipid peroxidation and acetaldehyde-protein adduct formation, further disrupting cytoskeletal and membrane function
•Antigenic alteration of hepatocytes & hepatic proteins, inducing an immunologic attack
Alcohol-induced fibrosis:
•Multifactorial and poorly understood
•Other effects of alcohol:
•Malnutrition & vitamin deficiencies
•Impaired digestive function (chronic gastric and intestinal mucosal damage and pancreatitis)
What is alcoholic steatosis
Lipid droplets accumulate in hepatocytes
•2 histologic types:
•Microvesicular
•Macrovesicular
•Initially centrilobular
•Later panlobular
•Large (4-6 kg) soft yellow greasy appearance
•Completely reversible if there is abstention
What is alcoholic hepatitis
Hepatocyte swelling (ballooning) due to accumulation of fat and water, and cell necrosis
•Mallory bodies: characteristic eosinophilic cytoplasmic inclusions (cytokeratin intermediate filaments)
What is hepatic cirrhosis
Initially, the liver is yellow- tan, fatty and enlarged
•Eventually, it becomes brown, shrunken and non-fatty
•Fibrous septa become thicker and extend through sinusoids
What are clinical features of alcoholic liver disease
Hepatic steatosis
•Asymptomatic
•Mild ↑ serum bilirubin and alkaline phosphatase
•Alcoholic hepatitis
•Minimal to severe manifestations
•Nonspecific symptoms
•Increase in serum bilirubin, alkaline phosphatase, WBCs
•Alcoholic cirrhosis
•Similar to other forms of cirrhosis
What are the prognosis of alcoholic liver disease
Variable outcome depending on severity of histologic changes
•5 years survival approaches 90% in abstainers who are free of jaundice, ascites, or hematemesis, but drops to 50-60% in those who continue to drink
• Immediate causes of death:
•hepatic failure
•massive GI hemorrhage
•intercurrent infection
•hepatorenal syndrome
•hepatocellular carcinoma
What is NAFLD
The most common metabolic liver disease and most common cause of incidental elevation of serum transaminases.
•A condition in which fatty liver develops in individuals who do not drink alcohol.
•May present as steatosis or as nonalcoholic steatohepatitis (NASH) which is similar to Alcoholic Steatohepatitis.
•Is considered as a significant contributor to the group of patients with cryptogenic cirrhosis.
•NAFLD & NASH are consistently associated with insulin resistance.
What is NAFLD
Other conditions associated with NAFLD:
•Type 2 D.M
•Obesity
•Dyslipidemia (increase triglycerides, low HDL, high LDL)
What are the pathogenesis and clinical features
Pathogenesis and clinical features:
•Insulin resistance results in accumulation of TGs in hepatocytes
•Fat-laden hepatocytes are sensitive to lipid peroxidation products leading to liver damage and inflammation
•Patients with steatosis are asymptomatic
•Patients with NASH may be asymptomatic, but some have fatigue, malaise, right upper discomfort or even symptoms of chronic liver disease.
Prognosis:
•The frequency of progression from steatosis to NASH and from NASH to cirrhosis seems to be low.
What is jaundice
ellowish discoloration of skin and sclera (icterus) due to systemic retention of bilirubin (> 2 mg/dl)
•Equilibrium between bilirubin production and clearance is disturbed:
•Excessive production
•Reduced hepatocellular uptake
•Impaired conjugation
•Decreased hepatocellular excretion
•Impaired bile flow
•Kernicterus: accumulation of bilirubin in brain
What is unconjugated bilirubin
UNCONJUGATED BILIRUBIN
•Water-insoluble
•Tightly complexed to serum albumin
•Cannot be excreted in urine
•Free form is toxic
•Lab test: Total bilirubin minus direct bilirubin
What is conjugated bilirubin
Water-soluble
•Loosely bound to serum albumin
•Excess amounts are excreted in urine
•Nontoxic
•Lab test: measured by direct bilirubin
What is cholestasis
Systemic retention of bilirubin and other solutes eliminated in bile (e.g. bile salts & cholesterol)
•Results from hepatocellular dysfunction and (intra- or extrahepatic) biliary obstruction
•Presents as jaundice, pruritis, skin xanthomas, malabsorption.
•Lab: Elevated bilirubin, alk. phosphatase, lipids
•Histology: bile pigment accumulation, foamy degeneration, bile duct distension and proliferation, bile lakes, portal tract fibrosis, cholangitis and cholangiolitis
•Types: - Intrahepatic - Extrahepatic
What is the pathology of cholestasis
Accumulation of bile pigment within hepatic parenchyma
•Hepatocyte swelling and foamy degeneration Bile duct proliferation secondary to biliary tree obstruction
•Hepatocyte necrosis, bile lakes, & portal tract fibrosis
What is pediatric liver diseases neonatal cholestasis
Prolonged conjugated hyperbilirubinemia in the newborn
•Major causes:
•EHBA & neonatal hepatitis
•Bile duct obstruction: Extrahepatic biliary atresia (EHBA)
•Neonatal infections: CMV, sepsis, UTI, syphilis
•Toxic: drugs, parenteral nutrition
•Metabolic diseases: tyrosinemia, Niemann-Pick disease, galactosemia, cystic fibrosis, ..
•Miscellaneous: shock, hypoperfusion, Alagille’s syndrome (paucity of bile ducts), ..
•Idiopathic neonatal hepatitis
Clinical presentation is typical: jaundice, dark urine, light stools, hepatomegaly
•Neonatal hepatitis may be primary (idiopathic) or secondary Idiopathic neonatal hepatitis (50-60%), extrahepatic biliary atresia (20%) & AAT deficiency (15%)
•Distinction between these disorders is essential because management is different • Liver biopsy is important in the diagnosis
What is the tumors of the liver cell adenoma
Mostly in young women with history of oral contraceptive pills (OCP) use.
•Well-demarcated yellow-tan frequently bile-stained nodule(s), often located beneath capsule, usually small in size but may reach up to 30 cm.
•Histology: sheets & cords of cells that resemble normal hepatocytes with minimal pleomorphism.
•Clinical significance:
•Misdiagnosed as hepatocellular carcinoma
•May rupture & cause serious intra-abdominal
What are some tumors of the liver
Hepatocellular carcinoma (hepatoma) Cholangiocarcinoma
•Tumors of mixed cell types
•• Hepatoblastoma - Aggressive tumor of children
•Angiosarcoma - Association with exposure to vinyl chloride, arsenic & Thorotrast
•Primary lymphomas, sarcomas, etc
What is hepatocellular carcinoma
Malignant tumor arising from hepatocytes
•Wide variation in geographic distribution
•Chronic HBV carrier state: a 200x increased risk
•HCC is frequently associated with cirrhosis
•M:F ratio ranges from 3:1 to 8:1
•Pathogenesis: several factors are - Viruses: HBV, HCV Chemicals: alcohol, food hepatocarcinogens (e.g. Aspergillus flavus aflatoxins B1) - Chronic liver disease
The HBV link: - HBV genome does not contain any oncogenic sequences, & there is no selective site of integration of viral DNA into host genome
•Repeated cycles of cell death & regeneration leads to accumulation of mutations & genomic instability
•HBV genome encode the X-protein, a transcriptional activator of many genes which may disrupt normal growth control by activating host cell protooncogenes
•HBV proteins bind & inactivate p53 +
What are some clinical features of hepatic carcinoma
Asymptomatic hepatomegaly
•Patients with cirrhosis:
•Rapid increase in liver size
•Sudden worsening of ascites
•Appearance of bloody ascites
•Fever & pain
•Lab: alpha-fetoprotein: nonspecific tumor marker; >1000 ng/ml is highly suggestive of HCC
•Px: grim: Death within 6 mths 1 yr due to:
•Severe cachexia,
•GI bleeding
•liver failure
•tumor rupture
What is the pathology of a hepatocellular carcinoma
Unifocal, multifocal or diffusely infiltrative tumor involving entire liver
•Cirrhosis of surrounding liver parenchyma is frequently present
•Strong propensity for invasion of vascular channels
HISTOPATHOLOGY OF HEPATOCELLULAR CARCINOMA
• Range from well- differentiated to anaplastic
•Neoplastic cells of well-differentiated tumors resemble hepatocytes and may show intra- cytoplasmic bile globules
•Fibrolamellar variant: better prognosis
What is a cholangiocarcinoma
Malignant epithelial neoplasms of bile duct origin
•Less common than hepatocellular carcinoma
•Not associated with etiologic factors related to HCC
•Etiology: Majority of cases are not associated with any known risk factor
•Radiologic contrast material:
•Thorostrast exposure
•Opisthorchis sinensis infestation of biliary tract
•Primary sclerosing cholangitis
What is the pathology of cholangiocarcinoma
Usually single tumor with a firm gritty consistency
•May be located in liver or biliary tree
•Papillary, intra- ductal or diffuse
• Klatskin tumor: present in the junction of hepatic & common bile ducts
HISTOPATHOLOGY OF CHOLANGIOCARCINOMA
Usually well- differentiated, forming glands and tubular structures Desmoplastic stroma
Bile pigment not present
May mimic metastatic adenocarcinoma
What is a secondary hepatic tumor
Metastatic tumours in the liver are more common than the primary hepatic tumours.
•Most frequently, they are bloodborne metastases
•Most frequent primary tumours metastasising to the liver, in descending order of frequency, are those of stomach, breast, lungs, colon, oesophagus, pancreas, malignant melanoma and haematopoietic malignancies.
•Sarcomas rarely metastasise to the liver.
What is the morphology of a secondary hepatic tumor
The tumour deposits are white, well-demarcated, soft or haemorrhagic. The surface of the liver shows characteristic umbilication due to central necrosis of nodular masses
•Histologically, the metastatic tumours generally reproduce the structure of the primary lesions
What are the disorders of the gallbladder
Cholelithiasis
•Cholecystitis
•Tumors Disorders of extrahepatic bile ducts
•Choledocholithiasis - Ascending cholangitis
•Extrahepatic biliary atresia
What is cholelithiasis
ommon disease affecting 10-20% of adults >80% are asymptomatic
•Two main types of gall stones: -
•Cholesterol stones
•Bilirubin calcium salts (pigment) stones
•Pathogenesis:
•bile supersaturation with cholesterol
•nucleation: promoted by calcium salts
•gall bladder stasis with cholesterol crystals remaining long enough to aggregate
What is the appearance of cholelithiasis
Cholesterol stones: exclusively in GB, ovoid firm, single or multiple, multi-faceted, most are radiolucent
•Pure: pale yellow
•Mixed: gray white to black, containing cacium carbonate, phosphates & bilirubin
•Pigment stones: anywhere in biliary tree, contain calcium salts of unconjugated bilirubin, calcium salts, mucin glycoproteins & cholesterol
•Black: in sterile GB bile, small, numerous, friable, 50-75% are radiopaque
•Brown in infected intra- or extrahepatic ducts, single or few
What are the clinical features of cholelithiasis
Clinical presentation:
•70-80% are asymptomatic
•Biliary pain, constant or colicky from an obstructed gallbladder or biliary tree
•Associated with inflammation of gallbladder
•Complications:
•Empyema
•Perforation
•Fistulae
•Inflammation of biliary tree
•Obstructive cholestasis
• Pancreatitis
•Intestinal obstruction (“gallstone ileus”)
What is the pathology of cholecystitis
Inflammation of the gallbladder
•Almost always associated with gallstones
•One of the most common indications for abdominal surgery
•Epidemiologic distribution similar to cholelithiasis
•Classification:
Acute calculous
Acute acalculous
Chronic
What are the types of acute cholecystitis
Acute calculous cholecystitis: caused by obstruction of GB neck or cystic duct by stones
•Chemical irritation & inflammation of GB wall
•Mucosal phospholipases hydrolyze biliary lecithin to lysolecithin
•Disruption of protective glycoprotein mucous layer
•Prostaglandin release within GB wall
•BF compromise due to GB distension & ↑ pressure
•Symptoms may be mild or sudden & severe
What is the pathology of acute cholecystitis
Enlarged (2-3x), tense GB with discolorations due to subserosal hemorrhages.
•Serosal fibrinous or suppurative exudate
•Stones obstructing GB neck or cystic duct in 90% GB lumen filled with turbid bile, +/- fibrin, hemorrhage & pus
•Empyema of gallbladder: full of pus
•Thickened edematous hyperemic wall
•Gangrenous cholecystitis: black necrotic GB
• Histology: edema, WBC infiltration, congestion & necrosis
What is the pathology of chronic cholecystitis
•+/- history of acute cholecystitis
•Gall stones almost always present, but stones & obstruction do not play major role in initiation of inflammation
•Supersaturation of bile predisposes to chronic inflammation & stone formation
•Bacteria are isolated in 1/3 of cases
•Variable morphologic appearance: minimal changes, contraction, enlargement, mucosal ulceration or wall thickening
What are some clinical features of cholecystitis
Acute & chronic calculous cholecystitis have similar & variable symptoms:
•minimal nonspecific symptoms to biliary colics to severe RUQ pain
•Fever, nausea, leukocytosis & prostration
•Conjugated hyperbilirubinemia
•Acute acalculous cholecystitis: symptoms obscured by general condition
•Dx: Ultrasonography
•Complications: cholangitis, sepsis, GB perforation, abscess, rupture, cholecyst-enteric fistula, intestinal ileus, …
What is gallbladder carcinoma
•Commonest extrahepatic biliary tract cancer
•Slightly commoner in women; peak 7th decade
•Due to recurrent trauma and inflammation: usually associated with stones; pyogenic or parasitic dis.
•Pathology: Infiltrating or fungating growth pattern
•Most are adenocarcinoma; 5% have squamous differentiation; minority are carcinoid tumors
•At dx, most have invaded liver, +/- cystic & biliary ducts, portahepatic LN
• Seeding to peritoneum, GIT, and lungs
•Insidious symptoms similar to cholelithiasis